Sir
The short arm of chromosome 8 is one of the most frequently altered in breast cancer. Chromosome 8p abnormalities have been associated with the development and/or progression of breast cancer and 8p22 deletions have been associated with more aggressive phenotypes and poorer survival (Yokota et al, 1999; Utada et al, 2000). Amplification of the region 8p12, that contains the neuregulin (NRG-1, also denominated heregulin) gene, is detected in about 12% of breast tumours (Adélaïde et al, 1994, 1998; Lee and Wood, 1993) and breakpoints in bands 8p11-p21 have been reported in breast cancer (Morris et al, 1997; Courtay-Cahen et al, 2000). The NRG-1 gene encodes, by alternative splicing or by initiation of gene transcripts at different sites, a family of more than 15 membrane bound or secreted proteins most of which contain an extracellular epidermal growth factor (EGF)-like domain (Peles and Yarden, 1993). These proteins act as ligands for the HER family of receptor tyrosine kinases and play an important role in cell growth and differentiation, morphogenesis and apoptosis (Burden and Yarden, 1997). Although NRG-1 was isolated during the search for a HER-2 ligand (Holmes et al, 1992), isoforms of NRG-1 bind to cells that express HER-3 or HER-4 receptors alone, heterodimers of HER-2 with either HER-3 or HER-4 but not to cells that express monomers of HER-2 (Burden and Yarden, 1997).
Much interest in the neuregulins is based on the fact that the receptors for these ligands, the HER family of proteins, are amplified or over-expressed in breast cancer. HER-2 (also known as neu and erbB2) gene amplification and/or over-expression are found in approximately one-third of breast tumours and have been associated with a poor prognosis (Lupu et al, 1996). NRG-1 induces an aggressive/invasive transformed morphology in cultured mammary epithelial cells that express HER-2 (Lupu et al, 1996) and can stimulate the growth of breast cancer cells that express low levels of the HER-2 receptor (Schaefer et al, 1997). Moreover, NRG-1 synthesised by the mesenchyme has been implicated in mammary development (Carraway et al, 1997), and it has been demonstrated that NRG-1 induces proliferation or differentiation of various mammary tumour cell lines, initiates programmed cell death and induces cell differentiation in breast tumours (Ram et al, 1995; Weinstein et al, 1998; Le et al, 2000). Recently, it has been identified in MDA-MB-175, a breast carcinoma cell line that shows elevated levels of HER-2 (Lewis et al, 1993), a translocation between chromosomes 8p12-21 and 11q13 that leads to the fusion of NRG-1 and DOC4 genes (Schaefer et al, 1997; Liu et al, 1999; Wang et al, 1999; Adélaïde et al, 2000). This translocation generates a new chimeric transcript that codes for a new isoform of the neuregulin family, denominated γ-heregulin (γ-HRG), that acts as an autocrine growth factor in the breast cancer cell line MDA-MB-175 (Schaefer et al, 1997).
In an attempt to define the incidence of this translocation in Spanish women with breast cancer we have studied this abnormality in a series of 141 breast carcinoma samples collected at the University Hospital of Salamanca. All tumour specimens were frozen immediately after removal and stored at −80°C before processing. DNA was extracted as described (Sánchez et al, 1995). The status of γ-HRG gene was assessed by Southern blot analysis. Genomic DNA was digested with the restriction endonuclease EcoRI and electrophoresed on 0.8% agarose gels. DNA was blotted and hybridised with a 538 bp SacII-XhoI fragment (nt 209–747 from sequence M94165) that spans the putative breakpoint site in chromosome 8p12.
Southern blot analysis of 141 primary breast carcinomas and the MCF-7 breast cancer cell line did not reveal any abnormal fragment. Our results show that the t(8;11)(p12;q13) translocation is not present in a large series of Spanish women with breast cancer and confirm previous reports that suggest that this translocation is a particularity of the MDA-MB-175 cell line and not a recurrent event (Wang et al, 1999; Adélaïde et al, 2000) indicating that γ-heregulin is not relevant in the development of breast cancer.
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References
Adélaïde J, Penault-Llorca F, Dib A, Yarden Y, Jacquemier J, Birnbaum D (1994) The Heregulin gene can be included in the 8p12 amplification unit in breast cancer. Genes Chromosomes Cancer 11: 66–69
Adélaïde J, Chaffanet M, Imbert A, Allione F, Geneix J, Popovici C, van Alewijk D, Trapman R, Zeillinger R, Borresen-Dale AL, Liderau R, Birnbaum D, Pébusque M-J (1998) Chromosome 8p11-p12 region: refined mapping and molecular alterations in breast cancer. Genes Chromosomes Cancer 22: 186–199
Adélaïde J, Chaffanet M, Mozziconacci M-J, Popovici C, Conte N, Fernández F, Sobol H, Jacquemier J, Pébusque M-J, Ron D, Lafage-Pochitaloff M, Birnbaum D (2000) Translocation and coamplification of loci from chromosome arms 8p and 11q in the MDA-MB-175 mammary carcinoma cell line. Int J Oncol 16: 683–688
Burden S, Yarden Y (1997) Neuregulins and their receptors: a versatile signalling module in organogenesis and oncogenesis. Neuron 18: 847–855
Carraway KL, Carraway CA, Carraway KL (1997) Roles of ErbB3 and ErbB4 in the physiology and pathology of the mammary gland. J Mammary Gland Biol Neoplasia 2: 187–198
Courtay-Cahen C, Morris JS, Edwards PAW (2000) Chromosome translocations in breast cancer with breakpoints at 8p12. Genomics 66: 15–25
Holmes WE, Sliwkowski MX, Akita RW, Henzel WJ, Lee J, Park JW, Yansura D, Abadi N, Raab H, Lewis GD, Shepard HM, Kuang W-J, Wood WI, Goeddel DV, Vandlen RL (1992) Identification of Heregulin, a specific activator of p185erbB2. Science 256: 1205–1210
Le X-F, McWatters A, Wiener J, Wu J-Y, Mills GB, Bast Jr RC (2000) Anti-HER2 antibody and heregulin suppress growth of HER2-overexpressing human breast cancer cells through different mechanisms. Clin Cancer Res 6: 260–270
Lee J, Wood WI (1993) Assignment of heregulin (HGL) to human chromosome 8p22-p11 by PCR analysis of somatic cell hybrid DNA. Genomics 16: 790–791
Lewis GD, Figari I, Fendly B, Wong WL, Carter P, Gorman C, Shepard HM (1993) Differential responses of human tumor cell lines to anti-p185HER2 monoclonal antibodies. Cancer Immunol Immunother 37: 255–263
Liu X, Baker E, Eyre HJ, Sutherland GR, Zhou M (1999) γ-Heregulin: a fusion gene of DOC-4 and neuregulin-1 derived from a chromosome translocation. Oncogene 18: 7110–7114
Lupu R, Cardillo M, Cho C, Harris L, Hijazi M, Perez C, Resenberg K, Yang D, Tang C (1996) The significance of heregulin in breast cancer tumor progression and drug resistance. Breast Cancer Res Treat 38: 57–66
Morris J, Carter N, Ferguson-Smith M, Edwards P (1997) Cytogenetic analysis of three breast carcinoma cell lines using reverse chromosome painting. Genes Chromosomes Cancer 20: 120–139
Peles E, Yarden Y (1993) Neu and its ligands: from an oncogene to neural factors. Bioessays 15: 815–824
Ram TG, Kokeny KE, Dilts CA, Ethier SP (1995) Mitogenic activity of neu differentiation factor/heregulin mimics that of epidermal growth factor and insulin-like growth factor-I in human mammary epithelial cells. J Cell Physiol 163: 589–596
Schaefer G, Fitzpatrick VD, Sliwkowski MX (1997) γ-Heregulin: a novel heregulin isoform that is an autocrine growth factor for the human breast cancer cell line, MDA-MB-175. Oncogene 15: 1385–1394
Sánchez I, San Miguel JF, Corral J, Martín C, Pérez R, González M, Cañizo MC, Orfao A, González-Sarmiento R (1995) Gene rearrangement in Acute non-lymphoblastic leukemia. Correlation with morphological and immunophenotypic characteristics of blast cells. Br J Haematol 89: 104–109
Utada Y, Haga S, Kajiwara T, Kasumi F, Sakamoto G, Nakamura Y, Emi M (2000) Allelic loss at the 8p22 region as a prognostic factor in large and estrogen receptor negative breast carcinoma. Cancer 88: 1410–1416
Wang X-Z, Jolicoeur EM, Conte N, Chaffanet M, Zhang Y, Mozziconacci M-J, Feiner H, Birnbaum D, Pébusque M-J, Ron D (1999) γ-heregulin is the product of a chromosomal translocation fusing the DOC4 and HGL/NRG1 genes in the MDA-MB-175 breast cancer cell line. Oncogene 18: 5718–5721
Weinstein EJ, Grimm S, Leder P (1998) The oncogene heregulin induces apoptosis in breast epithelial cells and tumors. Oncogene 17: 2107–2113
Yokota T, Yoshimoto M, Kasumi F, Sakamoto G, Nakamura Y, Emi M (1999) Localization of a tumor suppressor gene associated with the progression of human breast carcinoma within a 1-cM interval of 8p22-p23.1. Cancer 85: 447–452
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Supported by Grants from Junta de Castilla y Leon (SA81/00B), CICYT–FEDER (IFD97-1120) and Fundación Científica de la Asociación Española Contra el Cáncer.
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Sánchez-Valdivieso, E., Cruz, J., Salazar, R. et al. γ-Heregulin has no biological significance in primary breast cancer. Br J Cancer 86, 1362–1363 (2002). https://doi.org/10.1038/sj.bjc.6600245
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DOI: https://doi.org/10.1038/sj.bjc.6600245
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